1. Field of the Invention
The invention is in the field of methods of treating and preventing potassium imbalance by regulating ROMK endocytosis.
2. Description of Related Art
Pharmacotherapy has progressed rapidly over the last 20 years with the result that general practitioners more and more often use drugs which may influence potassium metabolism at the kidney or gastrointestinal level, or the transmembrane transport of potassium at the cellular level. Potassium abnormalities may result in life-threatening clinical conditions.
Potassium is the most abundant intracellular cation. It is critically important for many physiologic processes, including maintenance of cellular membrane potential, homeostasis of cell volume, and transmission of action potentials in nerve cells. Small changes in the extracellular potassium level can have profound effects on the function of the cardiovascular and neuromuscular systems. Nearly 98% of potassium is intracellular, with the concentration gradient maintained by the sodium- and potassium-activated adenosine triphosphatase (Na+/K+-ATPase) pump. The normal potassium level is 3.5-5.0 mEq/L, and total body potassium stores are approximately 50 mEq/kg (3500 mEq in a 70-kg person).
Potassium is eliminated through the gastrointestinal tract and the kidney. The kidneys play the major role in maintaining internal body potassium balance. Typically, they excrete 92% of the potassium ingested in the diet. Most importantly, the rate of potassium excretion is regulated in response to changes in dietary intake of potassium. Adaptive regulatory mechanisms ensure that excretion is precisely regulated to be equivalent to intake even when potassium intake increases by as much as 20 times. The primary control over urinary excretion of potassium takes place in the distal tubule and collecting duct system.
Renal elimination of potassium involves filtration, reabsorption, and secretion. Because potassium is unbound in the cell, it is freely filtered by the glomerulus. The proximal tubule then typically reabsorbs about 65% of filtered potassium and Henle's loop reabsorbs another 25%. In both segments, reabsorption is a constant fraction of the amount that was filtered. In contrast, the distal nephron has the dual capacity to both reabsorb and secrete potassium. Furthermore, unlike the proximal tubule and loop of Henle, the rate of potassium reabsorption or secretion in the distal nephron is regulated by hormones, such as aldosterone, and other factors in response to changes in dietary potassium intake.
Minute-to-minute levels of potassium are controlled by intracellular to extracellular exchange, mostly by the sodium-potassium pump that is controlled by insulin and beta2 receptors. A balance of GI intake and renal potassium excretion achieves long-term potassium balance.
Hypokalemia is a condition of low potassium blood levels and is most frequently caused by loss of this electrolyte in the kidney (caused for example by thiazide, thiazide-like and loop diuretics, glucocorticoids) and in the gastrointestinal tract (caused for example by laxatives, diarrhea, vomiting, and external fistula). Hypokalemia can also be the result of an increased intracellular potassium influx induced by sympathicomimetics used mostly by patients with asthma, or by insulin overdosage in diabetic subjects. The leading symptoms of hypokalemia are skeletal and smooth muscle weakness and cardiac arrhythmias.
Hyperkalemia occurs when there is an abnormally elevated blood level of potassium. Extreme degrees of hyperkalemia are considered a medical emergency due to the risk of potentially fatal arrhythmias. One of the causes of hyperkalemia is renal insufficiency. Hyperkalemia may be caused by acute or end-stage renal failure, impaired tubular excretion of potassium, acidemia, and severe cellular injury (tumor lysis syndrome). Medication that interferes with urinary excretion of potassium can also cause hyperkalemia. Such medicines include many commonly prescribed drugs such as ACE inhibitors and angiotensin receptor blockers (ARBs) which are used to treat hypertension; certain potassium-sparing diuretics (e.g. amiloride and spironolactone); NSAIDs such as ibuprofen, naproxen, or celecoxib; immunosuppressants such as cyclosporin and tacrolimus; the antibiotic trimethoprim; and the antiparasitic drug pentamidine. Certain diseases are also associated with hyperkalemia, including Addison's disease, aldosterone deficiency, some forms of congenital adrenal hyperplasia; Type IV renal tubular acidosis (resistance of renal tubules to aldosterone), and Gordon's syndrome ((pseduohypoaldosteronism type II or “familial hypertension with hyperkalemia”), a rare genetic disorder caused by defective modulators of salt transporters. Hyperkalemia can also be caused by rhabdomyolysis, burns or any cause of rapid tissue necrosis, including tumor lysis syndrome, massive blood transfusion or massive hemolysis and transport of potassium ions out of cells caused by acidosis, low insulin levels, beta-blocker therapy, digoxin overdose, or the paralyzing anesthetic succinylcholine. Long term use of these drugs can lead to long term potassium imbalance and secondary hyperkalemia. Hyperkalemia may be the cause of severe injury of both skeletal and smooth muscle cells. The specific treatment counteracting hyperkalemia is a bolus injection of calcium salts and, when necessary, hemodialysis. Kokot F, and Hyla-Klekot L., Pol Arch Med. Wewn. 2008 July-August; 118(7-8):431-4. Patients with the rare hereditary condition of hyperkalemic periodic paralysis appear to have a heightened sensitivity of muscular symptoms that are associated with transient elevation of potassium levels. Episodes of muscle weakness and spasms can be precipitated by exercise or fasting in these subjects.
Current methods of treating hyperkalemia include calcium supplementation, which does not lower potassium but decreases myocardial excitability, protecting against life threatening arrhythmias. Another means of treatment is administration of IV insulin which causes potassium ions to leave the blood and go into cells, as a secondary effect of increased activity of the sodium-potassium ATPase. Bicarbonate therapy is effective in cases of metabolic acidosis, where it stimulates an exchange of cellular hydrogen ions for sodium ions, that in turn stimulates sodium-potassium ATPase. Salbutamol (albuterol, or Ventolin) which is a β2-selective catecholamine, can be administered by nebulizer to promote movement of potassium into cells. Another form of treatment is administering polystyrene sulfonate, which is a binding resin that binds potassium in the intestine and removes it from the body by defecation. However, this medication may cause diarrhea. While there are treatments for acute hyperkalemia, there is still a need for long term regulation of potassium balance in subjects who have a genetic predisposition to potassium imbalance, who take drugs that can cause an imbalance, and in patients with chronic renal imbalance to help maintain residual potassium secretion and prolong the time until dialysis is required.